Quinazoline derivatives for the treatment of cancer diseases

ABSTRACT

The present invention relates to the use of quinazolines of formula (I), 
                         
wherein the groups R a  to R d  have the meanings given in the claims and specification, in cancer therapy.

The present invention relates to the use of quinazolines of formula (I),

wherein the groups R^(a) to R^(d) have the meanings given in the claimsand specification, in cancer therapy.

BACKGROUND OF THE INVENTION

Compounds of formula (I) are disclosed in WO 02/50043, WO 2004/074263and WO 2005/037824 as dual inhibitors of erbb1 receptor (EGFR) and erbB2(Her2/neu) receptor tyrosine kinases, suitable for the treatment of e.g.benign or malignant tumours, particularly tumours of epithelial andneuroepithelial origin, metastasisation and the abnormal proliferationof vascular endothelial cells (neoangiogenesis), for treating diseasesof the airways and lungs which are accompanied by increased or alteredproduction of mucus caused by stimulation by tyrosine kinases, as wellas for treating diseases of the gastrointestinal tract and bile duct andgall bladder which are associated with disrupted activity of thetyrosine kinases. The disclosure of WO 02/50043, WO 2004/074263 and WO2005/037824 includes preparation as well as pharmaceutical formulationsof the compounds and is incorporated by reference regarding theseaspects. Furthermore, it is known for treatment of tumour diseases thatthe compounds may be used in monotherapy or in conjunction with otheranti-tumour therapeutic agents, for example in combination withtopoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g.vinblastine), compounds which interact with nucleic acids (e.g.cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g.tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.),cytokines (e.g. interferons) or antibodies.

SUMMARY OF THE INVENTION

It has been found that the compounds of formula (I) provide unexpectedadvantages in the treatment of cancer, e.g. superior efficacy and/orreduced side effects, especially in the treatment of several specificcancer-subindications.

A first aspect of the present invention therefore is a method oftreating cancer, preferably the specific cancer-subindications referredto hereinafter, said method comprising administering a therapeuticallyeffective amount of a compound of formula (I) to a patient in needthereof, optionally in combination with radiotherapy,radio-immunotherapy and/or tumour resection by surgery.

Any reference to a compound of formula (I) in connection with theinvention should be understood to include the tautomers, racemates,enantiomers and diastereomers thereof, if any, the mixtures thereof aswell as the pharmacologically acceptable acid addition salts, solvates,hydrates, polymorphs, physiologically functional derivatives or prodrugsthereof.

The expression “patient” relates to a human or non-human mammalianpatient suffering from cancer and thus in need of such treatment,preferably the patient is a human person. Furthermore, the expression“patient” should be understood to include such cancer patients carryingtumors with wild-type EGF receptor as well as pre-selected cancerpatients with tumors harboring activating EGFR mutations. These can belocated in the tyrosine kinase domain of the EGF receptor such as forinstance the L858R or L861 point mutations in the activation loop (exon21), or in-frame deletion/insertion mutations in the ELREA sequence(exon 19), or substitutions in G719 situated in the nucleotide bindingloop (exon 18). Additional activating mutations have been reported inthe extracellular domain of the EGF receptor in various indications(e.g. EGFR vIII displaying exon 2-7 deletions). Other mutations such asthe T790M point mutation in exon 20 as well as certain exon 20insertions (e.g. D770_N771insNPG) which confer resistance to particulardrugs should also be included, as well as double mutants such as thecombined L858R/T790M mutation or the exon-19-del/T790M.

The expression “patient” should be understood to include also suchcancer patients carrying tumors with wild-type HER2 receptor as well aspre-selected cancer patients with tumors harboring activating HER2mutations, e.g. M774_A775insAYVM.

The indication “cancer” as used in the context of the invention is to beunderstood in a most general sense as a disease characterized byinappropriate cellular proliferation, migration, apoptosis orangiogenesis, preferably by inappropriate cellular proliferation.Inappropriate cell proliferation means cellular proliferation resultingfrom inappropriate cell growth, from excessive cell division, from celldivision at an accelerated rate and/or from inappropriate cell survival.

“Radiotherapy” means administering ionizing radiation to the patient, asconventionally used in cancer therapy. Radiotherapy may be appliedbefore, in parallel or after treatment by administration of a compoundof formula (I).

“Tumour resection by surgery” is one standard option in cancer therapyand may be applied before or after treatment by administration of acompound of formula (I).

A second aspect of the present invention is directed to the use of acompound of formula (I) for the manufacture of a medicament for thetreatment of cancer, preferably for the treatment of the specificcancer-subindications referred to hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: shows BIBW 2992 induces apoptosis in NCI-N87 gastric cancercells.

FIG. 2: shows the effect of BIBW 2992 on the growth of preexisting HNSCCFaDu xenografts.

FIG. 3: shows the effect of BIBW 2992 on the growth of MDA-MB-453 andSKOV-3 xenografts.

FIG. 4: shows the effect of BIBW 2992 on the growth of MDA-MB-453 andSKOV-3 xenografts.

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment (1), both with regard to the first and secondaspect of the invention, formula (I)

is defined to encompass those compounds wherein

R^(a) denotes a benzyl, 1-phenylethyl or 3-chloro-4-fluorophenyl group,

R^(b) denotes a hydrogen atom or a C₁₋₄-alkyl group,

R^(c) denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,tetrahydrofuran-3-yl-oxy, tetrahydrofuran-2-yl-methoxy,tetrahydrofuran-3-yl-methoxy, tetrahydropyran-4-yl-oxy ortetrahydropyran-4-yl-methoxy group,

R^(d) denotes a dimethylamino, N-cyclopropyl-N-methyl-amino,N-cyclopropylmethyl-N-methyl-amino, N-ethyl-N-methyl-amino,N,N-diethylamino, N-isopropyl-N-methyl-amino,N-(2-methoxyethyl)-N-methyl-amino,N-(1-methoxy-2-propyl)-N-methyl-amino,N-(3-methoxypropyl)-N-methyl-amino, pyrrolidino, 2-methylpyrrolidino,2-(methoxymethyl)-pyrrolidino, morpholino,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,(1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,N-cyclopropyl-N-methyl-amino-, N-methyl-N-(tetrahydrofuran-3-yl)-amino,N-methyl-N-(tetrahydrofuran-2-ylmethyl)-amino,N-methyl-N-(tetrahydrofuran-3-yl-methyl)-amino,N-methyl-N(tetrahydropyran-4-yl)-amino orN-methyl-N-(tetrahydropyran-4-yl-methyl)-amino group, or a group offormula (II)

wherein R^(e) and R^(f), which may be identical or different, in eachcase denote a hydrogen atom or a C₁₋₃-alkyl group,optionally in form of its tautomers, racemates, enantiomers,diastereomers and the mixtures thereof and optionally in form of thepharmacologically acceptable acid addition salts, solvates, hydrates,polymorphs, physiologically functional derivatives or prodrugs thereof.

In a second embodiment (2), both with regard to the first and secondaspect of the invention, formula (I)

is defined to encompass those compounds wherein

R^(a) denotes a 3-chloro-4-fluorophenyl group,

R^(b) denotes a hydrogen atom,

R^(c) denotes a cyclopropylmethoxy, cyclobutyloxy, cyclopentyloxy,tetrahydrofuran-3-yl-oxy, tetrahydrofuran-2-yl-methoxy,tetrahydrofuran-3-yl-methoxy, tetrahydropyran-4-yl-oxy ortetrahydropyran-4-yl-methoxy group,

R^(d) denotes a dimethylamino, N-cyclopropyl-N-methyl-amino,N-cyclopropylmethyl-N-methyl-amino, N-ethyl-N-methyl-amino,N,N-diethylamino, N-isopropyl-N-methyl-amino,N-(2-methoxyethyl)-N-methyl-amino,N-(1-methoxy-2-propyl)-N-methyl-amino,N-(3-methoxypropyl)-N-methyl-amino, pyrrolidino, 2-methylpyrrolidino,2-(methoxymethyl)-pyrrolidino, morpholino,(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,(1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl,N-methyl-N-(tetrahydrofuran-3-yl)-amino,N-methyl-N-(tetrahydrofuran-2-yl-methyl)-amino,N-methyl-N-(tetrahydrofuran-3-yl-methyl)-amino,N-methyl-N-(tetrahydropyran-4-yl)-amino orN-methyl-N-(tetrahydropyran-4-yl-methyl)-amino group, or a group offormula (II)

-   -   wherein R^(e) and R^(f) denote a hydrogen atom.

In a third embodiment (3), both with regard to the first and secondaspect of the invention, formula (I)

is defined to encompass those compounds wherein

R^(a) denotes a 3-chloro-4-fluorophenyl group,

R^(b) denotes a hydrogen atom,

R^(c) denotes a tetrahydrofuran-3-yl-oxy, tetrahydrofuran-2-yl-methoxy,tetrahydrofuran-3-yl-methoxy, tetrahydropyran-4-yl-oxy ortetrahydropyran-4-yl-methoxy group,

R^(d) denotes a dimethylamino, N-cyclopropyl-N-methyl,N-ethyl-N-methyl-amino, N,N-diethylamino, N-isopropyl-N-methyl-amino,morpholino, (1S,4S)-2-oxa-5-aza-bicyclo-[2.2.1]hept-5-yl or(1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, group, or a group offormula (II)

-   -   wherein R^(e) and R^(f) denote a hydrogen atom.

In a fourth embodiment (4), both with regard to the first and secondaspect of the invention, formula (I)

is defined to encompass those compounds wherein

R^(a) denotes a 3-chloro-4-fluorophenyl group,

R^(b) denotes a hydrogen atom,

R^(c) denotes a tetrahydrofuran-3-yl-oxy, tetrahydrofuran-2-yl-methoxyor tetrahydrofuran-3-yl-methoxy group,

R^(d) denotes a dimethylamino group or a group of formula (II)

-   -   wherein R^(e) and R^(f), denote a hydrogen atom.

In a fifth embodiment (5), both with regard to the first and secondaspect of the invention, formula (I) is defined to encompass thecompounds selected from the group consisting of

-   (a)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxy-quinazoline,-   (b)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   (c)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,-   (d)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,-   (e)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(tetrahydropyran-4-yloxy)-quinazoline,-   (f)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (g)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]-quinazoline,-   (h)    4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   (i)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (j)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (k)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,-   (l)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(N-ethyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,-   (m)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(N-isopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,-   (n)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   (o)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(N,N-diethyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   (p)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]-hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,-   (q)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((1R,4R)-2-oxa-5-aza-bicyclo[2.2.1]-hept-5-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline    and-   (r)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline.

In a sixth embodiment (6), both with regard to the first and secondaspect of the invention, the compounds of formula (I) are selected fromthe group consisting of

-   (d)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,

-   (k)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,    the dimaleate salt of compound (d) being especially preferred:-   (d′)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    dimaleate.

In a preferred embodiment the invention relates to the use of a compoundof formula (I) according to the invention, wherein the disease is cancerselected from the group consisting of carcinomas, sarcomas, melanomas,myelomas, hematological neoplasias, lymphomas and childhood cancers.

Examples of carcinomas within the scope of the invention include but arenot limited to adenocarcinoma (AC), squamous cell carcinoma (SCC) andmixed or undifferentiated carcinomas. Carcinomas within the scope of theinvention include but are not limited to the following histologies:

-   -   Head and neck tumours: SCC, AC, transitional cell cancers,        mucoepidermoid cancers, undifferentiated carcinomas;    -   Central nervous system tumours: Astrocytoma, glioblastoma,        meningeoma, neurinoma, schwannoma, ependymoma, hypophysoma,        oligodendroglioma, medulloblastoma;    -   Bronchial and mediastinal tumours:        -   Bronchial tumours:            -   Small cell lung cancers (SCLC): oat-cell lung cancer,                intermediate cell cancer, combined oat-cell lung cancer;            -   Non-small cell lung cancers (NSCLC): SCC, spindle cell                carcinoma, AC, bronchioalveolar carcinoma, large cell                NSCLC, clear cell NSCLC;        -   Mesothelioma;        -   Thymoma;        -   Thyroid carcinomas: papillary, follicular, anaplastic,            medullary;    -   Tumours of the gastrointestinal tract:        -   Oesophageal cancers: SCC, AC, anaplastic, carcinoid,            sarcoma;        -   Gastric cancers: AC, adenosquamous, anaplastic;        -   Colorectal cancers: AC, including hereditary forms of AC,            carcinoid, sarcoma;        -   Anal cancers: SCC, transitional epithelial cancer, AC, basal            cell carcinoma;        -   Pancreatic cancers: AC, including ductal and acinary            cancers, papillary, adenosquamous, undifferentiated, tumours            of the endocrine pancreas;        -   Hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma,            hepatoblastoma;        -   Biliary carcinomas: AC, SCC, small cell, undifferentiated;        -   Gastrointestinal stroma tumours (GIST);    -   Gynaecological cancers:        -   Breast cancers: AC, including invasive ductal, lobular and            medullary cancers, tubular, mucinous cancers,            Paget-carcinoma, inflammatory carcinoma, ductal and lobular            carcinoma in situ;        -   Ovarian cancers: Epithelial tumours, stroma tumours, germ            cell tumours, undifferentiated tumours;        -   Cervical cancers: SCC, AC, mixed and undifferentiated            tumours;        -   Endometrial cancers: AC, SCC, mixed, undifferentiated            tumours;        -   Vulvar cancers: SCC, AC;        -   Vaginal cancers: SCC, AC;    -   Urinary tract and testicular cancers:        -   Testicular cancers: seminoma;        -   Non-seminomatous germ cell tumours: teratoma, embryonal cell            carcinoma, choriocarcinoma, yolk sac tumour, mixed, Sertoli            and Leydig-cell tumours;        -   Extragonadal germ cell tumours;        -   Prostate cancers: AC, small cell, SCC;        -   Renal cell cancers: AC, including clear cell, papillary and            chromophobous carcinomas, hereditary forms (e.g.            von-Hippel-Lindau syndrome), nephroblastoma;        -   Urinary bladder cancers: transitional cell (urothelial)            cancers, SCC, AC;        -   Urethral cancers: SCC, transitional cell cancers, AC;        -   Penile cancers: SCC;    -   Tumours of endocrine tissue:        -   Thyroid cancers: papillary, follicular, anaplastic,            medullary carcinomas, including MEN syndrome;        -   Tumours of the endocrine pancreas;        -   Carcinoids;        -   Pheochromocytoma.

Examples of sarcomas within the scope of the invention include but arenot limited to Ewing-sarcoma, osteosarcoma or osteogenic sarcoma,chondrosarcoma, synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma,mesothelial sarcoma or mesothelioma, fibrosarcoma, angiosarcoma orhemangioendothelioma, liposarcoma, glioma or astrocytoma, myxosarcoma,malignant fibrous histiocytoma, mesenchymous or mixed mesodermal tumour,neuroblastoma and clear cell sarcoma.

Examples of melanomas within the scope of the invention include but arenot limited to superficial spreading melanoma, nodular andlentigo-maligna melanoma.

Examples of myelomas within the scope of the invention include but arenot limited to immunocytoma, plasmocytoma and multiple myeloma.

In another preferred embodiment the invention relates to the useaccording to the invention, wherein the hematological neoplasia isleukemia.

Further examples of hematologic neoplasias within the scope of theinvention include but are not limited to acute or chronic leukemias ofmyeloid, erythroid or lymphatic origin, myelodysplastic syndromes (MDS)and myeloproliferative syndromes (MPS, such as chronic myelogeneousleukemia, osteomyelofibrosis, polycythemia vera or essentialthrombocythemia).

Examples of lymphomas within the scope of the invention include but arenot limited to:

-   -   Hodgkin's-lymphoma;    -   Non-Hodgkin's-lymphomas: T- and B-cell lymphomas        -   B-cell lymphomas:            -   Low and intermediate grade: Chronic lymphocytic leukemia                (CLL), prolymphocytic leukemia (PLL), small lymphocytic                lymphoma, hairy cell leukemia, plasmacytoid lymphoma,                mantle cell lymphoma, follicular lymphoma, marginal zone                lymphoma including MALT-lymphoma;            -   High grade: diffuse large B-cell lymphoma (DLBCL                including immunoblastic and centroblastic variants),                lymphoblastic, Burkitt's lymphoma;        -   T-cell lymphomas:            -   Low grade: T-CLL, T-PLL, Mycosis fungoides,                Sezary-syndrome;            -   High grade: Anaplastic large cell, T-immunoblastic and                lymphoblastic.

In another preferred embodiment the invention relates to the useaccording to the invention, wherein the disease is cancer selected fromthe group consisting of mixed tumours, undifferentiated tumours andmetastases thereof.

Examples of mixed tumours within the scope of the invention include butare not limited to adenosquamous carcinomas, mixed mesodermal tumours,carcinosarcomas and teratocarcinomas.

Examples of undifferentiated, other tumours or metastases thereof withinthe scope of the invention include but are not limited toundifferentiated tumours, carcinomas of unknown primary (CUP),metastases of unknown primary (MUP) and pheochromocytoma, carcinoids.

Additionally the following tumour diseases which can be treated with acompound of formula (I) in accordance with the invention are summarized:

acral lentiginous melanoma, actinic keratoses, adenoid cycsticcarcinoma, adenomas, adenosarcoma, adrenocortical carcinoma,AIDS-related lymphoma, bartholin gland carcinoma, brain stem glioma,capillary carcinoma, central nervous system lymphoma, chondosarcoma,choriod plexus papilloma/carcinoma, cystadenoma, endodermal sinus tumor,endometrial hyperplasia, endometrial stromal sarcoma, endometrioidadenocarcinoma, epitheloid, focal nodular hyperplasia, gastrinoma,gestational trophoblastic tumor, glucagonoma, hepatic adenoma, hepaticadenomatosis, hypopharyngeal cancer, hypothalamic and visual pathwayglioma, insulinoma, intraepithelial neoplasia, interepithelial squamouscell neoplasia, intraocular invasive squamous cell carcinoma, large cellcarcinoma, islet cell carcinoma, Kaposi's sarcoma, laryngeal cancer,leukemia-related disorders, lip and oral cavity cancer, malignantmesothelial tumors, malignant thymoma, medulloepithelioma, merkel cellcarcinoma, mucoepidermoid carcinoma, multiple myeloma/plasma cellneoplasm, mycosis fungoides, myelodysplastic syndrome,myeloproliferative disorders, nasal cavity and paranasal sinus cancer,nasopharyngeal cancer, neuroepithelial adenocarcinoma, nodular melanoma,oat cell carcinoma, oligodendroglial, oral cancer, oropharyngeal cancer,pineal cell, pituitary tumors, pseudosarcoma, pulmonary blastoma,parathyroid cancer, pineal and supratentorial primitive neuroectodermaltumors, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma,retinoblastoma, serous carcinoma, small intestine cancer, soft tissuecarcinomas, somatostatin-secreting tumor, supratentorial primitiveneuroectodermal tumors, uveal melanoma, verrucous carcinoma, vipoma,Waldenstrom's macroglobulinemia, well differentiated carcinoma, andWilm's tumor.

In a further preferred embodiment (7), both with regard to the first andsecond aspect of the invention, the compounds of formula (I) areselected from the group consisting of

-   (a)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxy-quinazoline,-   (b)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,-   (c)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,-   (d)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    (BIBW2992),-   (e)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(tetrahydropyran-4-yloxy)-quinazoline,-   (f)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (g)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]-quinazoline,-   (h)    4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,-   (i)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (j)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,-   (k)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,    and-   (r)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,    and the cancer indication to be treated by administration of a    compound of formula (I) is selected from the group consisting of    -   Head and neck tumours: SCC, AC, transitional cell cancers,        mucoepidermoid cancers, undifferentiated carcinomas;    -   Central nervous system tumours: Astrocytoma, glioblastoma,        meningeoma, neurinoma, schwannoma, ependymoma, hypophysoma,        oligodendroglioma, medulloblastoma;    -   Bronchial and mediastinal tumours:        -   Bronchial tumours:            -   Non-small cell lung cancers (NSCLC): SCC, spindle cell                carcinoma, AC, bronchioalveolar carcinoma, large cell                NSCLC, clear cell NSCLC;        -   Thyroid carcinomas: papillary, follicular, anaplastic,            medullary;    -   Tumours of the gastrointestinal tract:        -   Oesophageal cancers: SCC, AC, anaplastic;        -   Gastric cancers: AC, adenosquamous, anaplastic;        -   Colorectal cancers: AC, including hereditary forms of AC,            carcinoid, sarcoma;        -   Pancreatic cancers: AC, including ductal and acinary            cancers, papillary, adenosquamous, undifferentiated, tumours            of the endocrine pancreas;        -   Hepatocellular cancers, cholangiocarcinoma    -   Gynaecological cancers:        -   Breast cancers: AC, including invasive ductal, lobular and            medullary cancers, tubular, mucinous cancers,            Paget-carcinoma, inflammatory carcinoma, ductal and lobular            carcinoma in situ;        -   Ovarian cancers: Epithelial tumours, stroma tumours, germ            cell tumours, undifferentiated tumours;    -   Urinary tract and testicular cancers:        -   Prostate cancers: AC, small cell, SCC;        -   Renal cell cancers: AC, including clear cell, papillary and            chromophobous carcinomas, hereditary forms (e.g.            von-Hippel-Lindau syndrome), Wilm's tumor, nephroblastoma;        -   Urinary bladder cancers: transitional cell (urothelial)            cancers, SCC, AC.

Examples of sarcomas within the scope of the invention include but arenot limited to Ewing-sarcoma, osteosarcoma or osteogenic sarcoma,chondrosarcoma, synovial sarcoma, leiomyosarcoma, rhabdomyosarcoma,mesothelial sarcoma or mesothelioma, fibrosarcoma, angiosarcoma orhemangioendothelioma, liposarcoma, glioma or astrocytoma, myxosarcoma,malignant fibrous histiocytoma, mesenchymous or mixed mesodermal tumour,neuroblastoma and clear cell sarcoma.

In a very preferred embodiment (8), both with regard to the first andsecond aspect of the invention, the compounds of formula (I) areselected from the group consisting of

-   (d)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    (BIBW2992),-   (k)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,    the dimaleate salt of compound (d) being especially preferred:-   (d′)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    dimaleate (BIBW2992 MA₂),    and the cancer indication to be treated by administration of a    compound of formula (I) is selected from the group consisting of    -   Head and neck tumours: SCC, AC, transitional cell cancers,        mucoepidermoid cancers, undifferentiated carcinomas;    -   Colorectal cancers, metastatic or non-metastatic: AC, including        hereditary forms of AC, carcinoid, sarcoma;    -   Pancreatic cancers: AC, including ductal and acinary cancers,        papillary, adenosquamous, undifferentiated, tumours of the        endocrine pancreas;    -   Breast cancers, metastatic or non-metastatic: AC, including        invasive ductal, lobular and medullary cancers, tubular,        mucinous cancers, Paget-carcinoma, inflammatory carcinoma,        ductal and lobular carcinoma in situ;    -   Prostate cancers: AC, small cell, SCC;    -   Gastric cancers: AC, adenosquamous, anaplastic;    -   Ovarian cancer;    -   Non-small cell lung cancers (NSCLC): SCC, spindle cell        carcinoma, AC, bronchioalveolar carcinoma, large cell NSCLC,        clear cell NSCLC.

It is known that cancer patients carrying activating EGFR mutations intheir tumors, i.e. within the tyrosine kinase domain of the EGFreceptor, may show increased sensitivity to treatment with EGFRinhibitors. Analogously, cancer patients carrying activating HER2mutations, e.g. M774_A775insAYVM, in their tumors may show increasedsensitivity to treatment with HER2 inhibitors. Both groups of patientsas well as a subgroup carrying both activating EGFR and HER2 mutationsmay show increased sensitivity to treatment with dual inhibitors oferbb1 receptor (EGFR) and erbB2 (Her2/neu).

The presence of specific gain-of-function mutations within the tyrosinekinase domain of the EGF receptor in a subgroup of NSCLC patients hasbeen associated with increased sensitivity to treatment with gefitiniband erlotinib (Lynch, New England Journal Medicine 350, 2129 (2004);Paez, Science 304, 1497 (2004); Pao, Proceedings of the National Academyof Science of the United States 101, 13306 (2004)). In particular, theL858R point mutation (exon 21) as well as deletion/insertion mutationsin the ELREA sequence (exon 19) account for the majority of gefitinibresponders. A secondary point mutation in exon 20, T790M, is associatedwith acquired resistance to gefitinib or erlotinib. This mutation isanalogous to the T315I mutation identified in CML patients who relapseunder imatinib treatment (imatinib resistant patients).

Irreversible inhibitors (e.g., HKI-272 or CL 387,785), in contrast toreversible inhibitors (e.g., gefitinib), are able to inhibitproliferation and EGF-induced EGFR phosphorylation in cell linesexpressing double mutant EGF receptors (Kwak, Proceedings of theNational Academy of Science of the United States 102, 7665 (2005) andKobayashi, New England Journal Medicine 352, 786 (2005)).

Any aspect of the present invention therefore includes, as a sub-aspect,optional pre-selection of cancer patients for an EGFR mutation in thetyrosine kinase domain of the EGF receptor as well as pre-selection ofcancer patients for an HER2 mutation. The EGFR mutations preferablyrelevant in in this context are selected from the group consisting ofthe L858R and L861 point mutations in the activation loop (exon 21),in-frame deletion/insertion mutations in the ELREA sequence (exon 19),substitutions in G719 situated in the nucleotide binding loop (exon 18),activating mutations in the extracellular domain of the EGF receptorsuch as EGFR vIII displaying exon 2-7 deletions, the T790M pointmutation in exon 20, exon 20 insertions such as D770_N771insNPG, anddouble mutants such as the combined L858R/T790M mutation and theexon-19-del/T790M. The HER2 mutation preferably relevant in in thiscontext is the M774_A775insAYVM mutation.

Methods for detecting mutations in the tyrosine kinase domain of the EGFreceptor are known in the art, several corresponding diagnostic toolsare approved by the FDA and commercially available, e.g. an assay forthe detection of epidermal growth factor receptor mutations in patientswith non-small cell lung cancer (Genzyme Corp.; see also Journal ofClinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-MeetingEdition). Vol 24, No 18S (June 20 Supplement), 2006: Abstract 10060).

Any of the embodiments of the invention mentioned hereinbefore definingcompounds of formula (I) and cancer indications applies accordingly tothe optional sub-aspect of pre-selection of cancer patients for anactivating EGFR mutation in the tyrosine kinase domain of the EGFreceptor and/or pre-selection of cancer patients for an activating HER2mutation. Treatment of EGFR mutant cancer patients with the compounds offormula (I) may allow a response in cancer patients with acquired orpersistent resistance to gefitinib or erlotinib treatment. Treatment ofcancer patients carrying an activating HER2 mutant in their tumors withthe compounds of formula (I) may allow a responce in cancer patientswith acquired or persistent resistance to certain chemotherapeutics suchas e.g. lapatinib or herceptin.

Most preferred cancer indications with EGFR or HER2 mutations relevantin connection with the sub-aspect of patient pre-selection for mutationsare selected from the group consisting of

-   -   Head and neck tumours: SCC, AC, transitional cell cancers,        mucoepidermoid cancers, undifferentiated carcinomas;    -   Colorectal cancers, metastatic or non-metastatic: AC, including        hereditary forms of AC, carcinoid, sarcoma;    -   Pancreatic cancers: AC, including ductal and acinary cancers,        papillary, adenosquamous, undifferentiated, tumours of the        endocrine pancreas;    -   Breast cancers, metastatic or non-metastatic: AC, including        invasive ductal, lobular and medullary cancers, tubular,        mucinous cancers, Paget-carcinoma, inflammatory carcinoma,        ductal and lobular carcinoma in situ;    -   Prostate cancers: AC, small cell, SCC;    -   Gastric cancers: AC, adenosquamous, anaplastic;    -   Ovarian cancer;    -   Non-small cell lung cancers (NSCLC): SCC, spindle cell        carcinoma, AC, bronchioalveolar carcinoma, large cell NSCLC,        clear cell NSCLC,        but especially    -   Non-small cell lung cancers (NSCLC): SCC, spindle cell        carcinoma, AC, bronchioalveolar carcinoma, large cell NSCLC,        clear cell NSCLC, especially metastatic, second line patients        who have failed at least one prior chemotherapy regimen or        3rd/4th line patients who have received Tarceva or Iressa for at        least 12 weeks and then failed,        preferably to be treated by administration of a compound of        formula (I) selected from the group consisting of:

-   (a)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxy-quinazoline,

-   (b)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,

-   (c)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,

-   (d)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline    (BIBW2992),

-   (e)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-(tetrahydropyran-4-yloxy)-quinazoline,

-   (f)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (g)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-3-yl)methoxy]-quinazoline,

-   (h)    4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,

-   (i)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (j)    4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,

-   (k)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,    and

-   (r)    4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,    or a pharmaceutically acceptable salt thereof.

The first aspect of the present invention therefore includes, as asub-aspect (A), a method of treating cancer comprising pre-selection ofcancer patients for EGFR and/or HER2 mutations and administering atherapeutically effective amount of a compound of formula (I) to apre-selected cancer patient shown to carry an EGFR mutation in thetyrosine kinase domain of the EGF receptor and/or with a tumor harboringan activating HER2 mutation, optionally in combination withradiotherapy, radio-immunotherapy and/or tumour resection by surgery.

Accordingly, the second aspect of the present invention includes, as asub-aspect (B), the use of a compound of formula (I) for the manufactureof a medicament for the treatment of cancer in a pre-selected cancerpatient shown to carry an EGFR mutation in the tyrosine kinase domain ofthe EGF receptor and/or with a tumor harboring an activating HER2mutation.

Method of Treatment:

The method of treatment according to the invention comprisesadministration of a therapeutically effective amount of a compound offormula (I), optionally in form of its tautomers, racemates,enantiomers, diastereomers and the mixtures thereof and optionally inform of the pharmacologically acceptable acid addition salts, solvates,hydrates, polymorphs or physiologically functional derivatives thereof,to a patient in need thereof, wherein the active ingredient isadministered orally, enterically, transdermally, intravenously,peritoneally or by injection, preferably orally. The patient preferablyis a human patient.

Dosage:

The compounds of formula (I) may be administered to the human patient ina daily dose of 0.01-4 mg/kg of body weight (bw), preferably 0.1-2mg/kg, particularly preferred in a dose of 0.2-1.3 mg/kg bw. For oraltreatment the compounds of formula (I) may be administered daily in atotal dose of 10, 20, 30, 40, 50, 60, 70, 100, 200, or 300 mg,optionally divided into multiple doses, e.g. 1 to 3 doses to beadministered through the day. Preferably the oral daily dose isadministered only once a time. These doses can be applied with any ofthe compounds of formula (I), e.g. with BIBW2992 or an equivalent doseof BIBW2992MA₂ containing respective amounts of the active basecomponent. Especially for higher doses periods of treatment shouldalternate with periods of recovery, without administering the active offormula (I). For instance, treatment could follow a “7 day on-7 dayoff”, a “14 day on-14 day off”, a “21 day on 7 day off” or a continuousdosing schedule. “On-off” time periods can be chosen shorter, especiallyif higher doses are administered, or individually adapted to the needsof the patient. The dosage for intravenous use of a compound of formula(I), e.g. of BIBW2992MA₂ may be 1-1000 mg, preferably 5-300 mg,particularly preferred 10-100 mg (dosages refer to the base formBIBW2992), either given as a bolus or, especially if higher doses areapplied, as a slow intravenous infusion over several hours, e.g. overabout 1, 2, 4, 6, 10, 12 or 24 hours.

In one embodiment the invention relates to the method of treatmentdescribed above, characterised in that a compound of formula (I), or itspolymorph, metabolite, hydrate, solvate, an individual optical isomer,mixtures of the individual enantiomers or racemates thereof, or apharmaceutically acceptable salt thereof, is administered intermittentor in a daily dosage such that the plasma level of the active substancepreferably lies between 10 and 5000 nM for at least 12 hours of thedosing interval.

However, it may optionally be necessary to deviate from the amountsspecified, depending on the body weight or method of administration, theindividual response to the medication, the nature of the formulationused and the time or interval over which it is administered. Thus, insome cases, it may be sufficient to use less than the minimum quantityspecified above, while in other cases the upper limit specified willhave to be exceeded. When large amounts are administered it may beadvisable to spread them over the day in a number of single doses.

A compound of formula (I), its tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts, solvates,hydrates, polymorphs, physiologically functional derivatives or prodrugsthereof, may be used in monotherapy or combined with other activesubstances according to the invention, optionally also in conjunctionwith other pharmacologically active substances.

Pharmaceutical Formulations:

Suitable pharmaceutical preparations for the use in accordance with theinvention include, for example, tablets, capsules, suppositories,solutions, and particularly solutions for injection (s.c., i.v., i.m.)and infusion, syrups, emulsions or dispersible powders. The amount ofpharmaceutically active compound in each case should be in the rangefrom 0.1-90 wt. %, preferably 0.5-50 wt. % of the total composition,i.e. in amounts which are sufficient to achieve the dosage range givenbelow. The doses specified may, if necessary, be given several times aday.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharin, cyclamate, glycerol or sugar and a flavour enhancer,e.g. a flavouring such as vanillin or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection and infusion are prepared in the usual way, e.g.with the addition of preservatives such as p-hydroxybenzoates, orstabilisers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, while if water isused as the diluent organic solvents may optionally be used assolubilisers or auxiliary solvents, and transferred into injection vialsor ampoules or infusion bottles.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Suitable excipients may be, for example, water, pharmaceuticallyacceptable organic solvents, such as paraffins (e.g. petroleumfractions), oils of vegetable origin (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolin, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silica and silicates),sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin,spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

The preparations are administered in the usual way, preferably by oralor transdermal route, particularly preferably by oral route. Whenadministered orally the tablets may, of course, contain additives, suchas e.g. sodium citrate, calcium carbonate and dicalcium phosphatetogether with various additives, such as starch, preferably potatostarch, gelatine and the like, in addition to the abovementionedcarriers. Lubricants such as magnesium stearate, sodium laurylsulphateand talc may also be used to form tablets. In the case of aqueoussuspensions the active substances may be combined with various flavourenhancers or colourings in addition to the abovementioned excipients.For parenteral use, solutions of the active substances may be preparedusing suitable liquid carrier materials.

The following Examples serve to illustrate the invention withoutrestricting it:

Example 1 Molecular Potency and Selectivity of BIBW 2992 Compared toPrior Art Compounds

The data summarized in table 1 were obtained using standard in-solutionkinase assays performed at saturating ATP concentrations measuringincorporation of phosphate into poly (GluTyr). The same conditions wereused for the different compounds in any kinase assay for directcomparison. IC50 values were generated from 12-point dose-responsecurves run in triplicates.

TABLE 1 BIBW 2992 is a potent and selective dual inhibitor of the EGFRand HER2 kinases EGFR- HER2 β-InsR VEGFR-2 HGFR c-src Kinase KinaseKinase Kinase Kinase Kinase Code [nM] [nM] [nM] [nM] [nM] [nM] gefitinib(ZD-1839) 3 1100 >100000 >100000 >100000 >100000 erlotinib (OSI-774) 2238 >100000 >100000 >100000 >100000 canertinib (CI-1033) 0.3 30 >10000024900 >100000 1480 lapatinib (GW-2016) 315 >100000 >100000 >20000 >20000 BIBW 2992 0.5 14 >100000 >100000 13000>4000

Example 2 Inhibition of EGF-Induced EGFR, and Constitutive HER2 ReceptorPhosphorylation by BIBW 2992, Compared to Prior Art Compounds

EC50 values were generated from 12-point dose-response curves. Forreceptor phosphorylation assays cells were pre-incubated for 1 h withtest compound. Cells were then either stimulated with EGF (100 ng/ml for20 min) or directly harvested and tested for pEGFR or pHER2 by ELISA.Propidium iodide based assays were used to assess the proliferation ofBT-474 cells in vitro. The compounds were tested under conditionsallowing direct direct comparison.

Dual EGFR/HER2 inhibition results in more potent inhibition of cellularproliferation

TABLE 2 Cellular potency of BIBW 2992 Receptor Phosphorylation A431NIH3T3 N87 BT-474 Proliferation EGFR-PO₄ HER2-PO₄ HER2-PO₄ HER2-PO₄BT-474 Compound EC₅₀ [nM] EC₅₀ [nM] EC₅₀ [nM] EC₅₀ [nM] EC₅₀ [nM]gefitinib (ZD-1839) 35 2300 541 3710 1070 erlotinib (OsI-774) 5 734 468930 829 canertinib (CI-1033) 22 85 288 184 66 lapatinib (GW-2016) 105171 101 99 52 BIBW 2992 13 71 48 35 12

Example 3 Induction of Apoptosis by BIBW 2992

NCI-N87 gastric cancer cells were treated in vitro with 250 nM BIBW2992. At indicated time points cells were harvested and samples wereanalyzed for free nucleosomes (apoptosis hallmark) using the Cell deathELISA kit #1774425 from Roche Diagnostics. Results are shown in FIG. 1(Appendix).

The following Examples show that once daily dosing of BIBW 2992significantly inhibits, in a dose dependent manner, the growth of avariety of human tumor xenografts in nude mice:

Example 4 Effect of BIBW 2992 on the Growth of Preexisting HNSCC FaDuXenografts

Mice carrying established tumors (50-100 mm3) were treated orally, oncedaily at indicated doses. On the last day of treatment plasma sampleswere collected and analyzed for compound levels. Results are shown inFIG. 2 (Appendix).

Example 5 Effect of BIBW 2992 on the Growth of MDA-MB-453 and SKOV-3Xenografts

Mice carrying established tumors (50-100 mm3) were treated orally, oncedaily at indicated doses with the respective compounds. On the last dayof treatment plasma samples were collected and analyzed for compoundlevels. Results are shown in FIG. 3 (Appendix).

Example 6 Effect of BIBW 2992 on the Growth of Large NCI-N87 Xenografts

Mice carrying established tumors (Panel A: 50-100 mm3; Panel B: 450 mm3)were treated once daily p.o. with BIBW 2992 or once weekly i.v. withHerceptin at indicated doses. Daily oral treatment with BIBW 2992induces regression of NCI-N87 xenografts. Results are shown in FIG. 4(Appendix).

Example 7 Pharmacodynamic Evaluation of BIBW 2992 in Several XenograftModels

Mice carrying established tumors (50-100 mm³), were treated orally, oncedaily at indicated doses with the respective compounds. On the last dayof treatment plasma samples were collected and analyzed for compoundlevels.

Daily oral treatment with BIBW 2992 at a dose of 20 mg/kg results infull anti-tumor activity in various xenograft models. Results aresummarized in table 3.

TABLE 3 Model Dose [mg/kg/d] T/C [%] Cmax [nM] AUC [nM*h] A431 30 2 5874007 A431 20 2 285 3198 SKOV-3 20 3 236 2156 MDA-453 20 3 83 972 N87 204 80 1075 SKOV-3 15 13 83 589 N87 10 64 66 445 A431 10 80 87 382 A431 3100 8 21

The T/C (Treated/Control) value corresponds to a % of control value:

median value in the treated group in relation to median value of tumorsize in the control group (usually N=10) at the end of the experiment,set to 100% (e.g.: a median value in the treated group of 200 mm³ inrelation to a median value in the control group of 1000 mm³ results aT/C value of 20%).

Example 8 Response of Patients Treated with BIBW2992

(a) One female patient with metastatic adenocarcinoma of the lung(NSCLC) treated with BIBW2992 MA2 at 10 mg daily (dose refers to thebase form; continuous administration schedule) had a confirmed partialresponse after two months of treatment. The pulmonary lesions haveclearly shrunk by >35%, confirmed with a repeat CT scan in 4 weeks. CTscans done in regular intervals confirm the continuation of the partialresponse. The patient treated developed brain metastases on treatmentand increasing the dose of BIBW2992 to 40 mg daily has led to a responsein her cerebral disease. This patient remains on treatment 23 monthsafter starting BIBW 2992. This patient's tumour cells have a complexheterozygous EGFR mutation including a deletion and missense mutationsof 4-amino acids in the kinase domain, but a wildtype HER2 domain.

(b) Another female patient with non-small cell lung cancer, pleuraltumours and mediastinal lymph nodes treated with BIBW2992 MA2 alsotreated in a continuous dosing schedule at 40 mg daily did develop apartial response as measured by a CT scan after two months of treatment.Five target lesions had been identified; the sum thereof has gone downfrom 7.3 to 2.6 cm, a decrease of 65%. The patient remains in partialresponse 14 months after starting treatment with BIBW 2992. An in-framedeletion of 5 amino acids in the same region of the kinase domain hasbeen detected in this patient.

(c) Using a 14 day on 14 day off schedule 2 patients with parotidtumors, one patient with esophageal cancer, one patient with colorectalcancer, one patient with breast cancer, one patient with thyroid cancerand one patient with other endocrine cancer have had stable disease forat least 6 months and have been treated for more than 6 months.

(d) In a continuous dosing schedule and in addition to the abovementioned non-small cell lung cancer patients with partial remissions, apatient with thymic cancer (40 mg daily) and a patient with ovariancancer (20 mg daily) have had stable disease for at least six months.

(e) In a combined treatment schedule with docetaxel (given every 3weeks) and BIBW 2992 given for 3 days after the administration ofdocetaxel one patient had a complete response (breast cancer) and onehad partial response (oesophageal).

(f) In a combined treatment schedule with docetaxel (given every 3weeks) and BIBW 2992 given for 20 or 13 days after the administration ofdocetaxel, two patients had a partial responses (ovarian and non-smallcell lung cancer).

Example 9 Coated Immediate-Release Tablets Containing 75 mg of ActiveSubstance by Dry-Granulation Process

Composition:

1 tablet contains:

active substance 75.0 mg  calcium phosphate anhydrous 108.0 mg  cornstarch 35.5 mg  polyvinylpyrrolidone 10.0 mg  magnesium stearate 1.5 mghydroxypropylmethylcellulose 7.5 mg polyethylene glycol 1.0 mgpolydextrose 5.0 mg talc 1.0 mg pigments 0.5 mg water (volatile) 245.0mg Preparation:

The active substance is mixed with calcium phosphate, corn starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and half thespecified amount of magnesium stearate. Ribbons are produced in aroller-compactor and these are then rubbed through a screen with a meshsize of 1.5 mm using a suitable machine and mixed with the rest of themagnesium stearate. This granulate is compressed in a tablet-makingmachine to form tablets of the desired shape.

Weight of core: 230 mg

Tablet shape: 9 mm round, bi-convex

The tablet cores are subsequently coated with an aqueous film-coatconsisting essentially of hydroxypropylmethylcellulose, polyethyleneglycol, polydextrose, talc and pigments.

Weight of coated tablet: 245 mg.

Example 10 Extended-Release Tablets Containing 100 mg of ActiveSubstance by Organic Granulation Granulation Process

1 tablet contains:

active substance 100.0 mg lactose  34.0 mg hydroxypropylmethylcellulose  80 mg polyvinylpyrrolidone  4.0 mg magnesium stearate  2.0 mg ethanol(volatile) 220.0 mg

Preparation:

The active substance, lactose and hydroxypropylmethylcellulose are mixedtogether and uniformly moistened with solution of thepolyvinylpyrrolidone in ethanol. After the moist composition has beenscreened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. itis screened again (1.5 mm mesh size) and the lubricant is added. Thefinal blend is compressed to form tablets.

-   -   Weight of tablet: 220 mg    -   Tablet shape: 10 mm, flat-faced, with bevelled edges.

Example 11 Tablets Containing 150 mg of Active Substance by AqueousGranulation Process

1 tablet contains:

active substance 150.0 mg  powdered lactose 98.0 mg corn starch 40.0 mgcolloidal silica  1.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg 

Preparation:

The active substance mixed with lactose, corn starch is moistened with a20% aqueous polyvinylpyrrolidone solution and passed through a screenwith a mesh size of 1.5 mm. The granules, dried at 45° C., are passedthrough the same screen again and mixed with the specified amount ofmagnesium stearate and colloidal silica. Tablets are pressed fromthefinal blend.

Weight of tablet: 300 mg

-   -   Tablet shape: 14 mm×6.8 mm, oblong biconvex with embossement

Example 12 Hard Capsules Containing 150 mg of Active Substance inGranules

Composition:

1 capsule contains:

active substance 150.0 mg  microcrystalline cellulose 80.0 mg lactose(spray-dried) 87.0 mg colloidal silica 10.0 mg 320.0 mg 

Preparation:

The active substance is mixed with the excipients in a high-shear mixer,passed through a screen with a mesh size of 0.75 mm and homogeneouslymixed using a suitable apparatus. The finished mixture is packed intosize 1 hard gelatin capsules.

Capsule filling: 320 mg

Capsuleshape: size 1, opaque hard capsule.

Example 13 Hard Capsules Containing 150 mg of Active Substance as aLiquid Fill

Composition:

1 capsule contains:

active substance 150.0 mg groundnut oil 300.0 mg colloidal silica  10.0mg 460.0 mg

Preparation:

The active substance is dissolved in the excipient inside a homogenizerand the colloidal silica is added for adjustment of viscosity. Thefinished mixture is filled into size 1 hard gelatin capsules.

Capsule filling: 460 mg

Capsuleshape: size 0, opaque hard capsules.

Example 14 Suppositories Containing 150 mg of Active Substance

Composition:

1 suppository contains:

active substance 150.0 mg polyethyleneglycol 1500 550.0 mgpolyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate840.0 mg 2,000.0 mg 

Preparation:

After the suppository mass has been melted the active substance ishomogeneously suspended therein and the melt is poured into chilledmoulds.

Example 15 Suspension Containing 50 mg of Active Substance

Composition:

100 ml of suspension contain:

active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methylp-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 gglycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist.water ad 100.0 ml

Preparation:

The distilled water is heated to 70° C. The methyl and propylp-hydroxybenzoates together with the glycerol and sodium salt ofcarboxymethylcellulose are dissolved therein with stirring. The solutionis cooled to ambient temperature and the active substance is added andhomogeneously dispersed therein with stilling. After the sugar, thesorbitol solution and the flavouring have been added and dissolved, thesuspension is evacuated with stirring to eliminate air.

5 ml of suspension contain 50 mg of active substance.

Example 16 Ampoules Containing 10 mg Active Substance

Composition:

1 ampoule contains:

active substance 10.0 mg 0.01N hydrochloric acid. q.s  sodium chlorideq.s. double-distilled water ad 2.0 ml

Preparation:

The active substance is dissolved in the requisite amount of 0.01 N HCl,made isotonic with sodium chloride, filtered sterile and transferredinto 2 ml ampoules with subsequent steam sterilization.

Example 17 Ampoules Containing 50 mg of Active Substance

Composition:

1 ampoule contains:

active substance 50.0 mg 0.01N hydrochloric acid q.s. sodium chlorideq.s. double-distilled water ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with sodium chloride, filtered sterile and transferredinto 10 ml ampoules with subsequent steam sterilization.

Example 18 Capsules for Powder Inhalation Containing 5 mg of ActiveSubstance

Composition:

1 capsule contains:

active substance  5.0 mg lactose for inhalation 15.0 mg 20.0 mg

Preparation:

The active substance is mixed with lactose for inhalation. The mixtureis packed into capsules in a capsule-making machine (weight of the emptycapsule approx. 50 mg). weight of capsule: 70.0 mg size of capsule 3

Example 19 Solution for Inhalation for Hand-Held Nebulisers Containing2.5 mg Active Substance

Composition:

1 spray contains:

active substance 2.500 mg benzalkonium chloride 0.001 mg 1N hydrochloricacid q.s. 2.500 mg ethanol/water (50/50 m/m) ad 15.000 mg

Preparation:

The active substance and benzalkonium chloride are dissolved inethanol/water (50/50). The pH of the solution is adjusted with 1Nhydrochloric acid. The resulting solution is filtered sterile andtransferred into suitable containers for use in hand-held nebulisers(cartridges).

Contents of the container: 4.5 g

The invention claimed is:
 1. A method for treating metastatic non-smallcell lung cancer (NSCLC) of squamous histology in a second line patienthaving failed at least one prior chemotherapy regimen, the methodcomprising administering to said patient a therapeutically effectiveamount of the compound4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,or a physiologically acceptable salt thereof.
 2. The method of claim 1,wherein the4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,or a physiologically acceptable salt thereof, is used in monotherapy orin combination with another anti-tumour therapeutic agent.
 3. The methodof claim 2, wherein the other anti-tumour therapeutic agent is selectedfrom the group consisting topoisomerase inhibitors, mitosis inhibitors,compounds which interact with nucleic acids, hormone antagonists,inhibitors of metabolic processes, cytokines, and antibodies.
 4. Themethod of claim 2, wherein the other anti-tumour therapeutic agent iscis-platinum.
 5. The method of claim 2, wherein the compound is4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazolinedimaleate.